Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial.

BACKGROUND: Treatment inertia is a recognised barrier to blood pressure control, and simpler, more effective treatment strategies are needed. We hypothesised that a hypertension management strategy starting with a single pill containing ultra-low-dose quadruple combination therapy would be more effective than a strategy of starting with monotherapy. METHODS: QUARTET was a multicentre, double-blind, parallel-group, randomised, phase 3 trial among Australian adults (≥18 years) with hypertension, who were untreated or receiving monotherapy. Participants were randomly assigned to either treatment, that started with the quadpill (containing irbesartan at 37·5 mg, amlodipine at 1·25 mg, indapamide at 0·625 mg, and bisoprolol at 2·5 mg) or an indistinguishable monotherapy control (irbesartan 150 mg). If blood pressure was not at target, additional medications could be added in both groups, starting with amlodipine at 5 mg. Participants were randomly assigned using an online central randomisation service. There was a 1:1 allocation, stratified by site. Allocation was masked to all participants and study team members (including investigators and those assessing outcomes) except the manufacturer of the investigational product and one unmasked statistician. The primary outcome was difference in unattended office systolic blood pressure at 12 weeks. Secondary outcomes included blood pressure control (standard office blood pressure <140/90 mm Hg), safety, and tolerability. A subgroup continued randomly assigned allocation to 12 months to assess long-term effects. Analyses were per intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, ACTRN12616001144404, and is now complete. FINDINGS: From June 8, 2017, to Aug 31, 2020, 591 participants were recruited, with 743 assessed for eligibility, 152 ineligible or declined, 300 participants randomly assigned to intervention of initial quadpill treatment, and 291 to control of initial standard dose monotherapy treatment. The mean age of the 591 participants was 59 years (SD 12); 356 (60%) were male and 235 (40%) were female; 483 (82%) were White, 70 (12%) were Asian, and 38 (6%) reported as other ethnicity; and baseline mean unattended office blood pressure was 141 mm Hg (SD 13)/85 mm Hg (SD 10). By 12 weeks, 44 (15%) of 300 participants had additional blood pressure medications in the intervention group compared with 115 (40%) of 291 participants in the control group. Systolic blood pressure was lower by 6·9 mm Hg (95% CI 4·9-8·9; p<0·0001) and blood pressure control rates were higher in the intervention group (76%) versus control group (58%; relative risk [RR] 1·30, 95% CI 1·15-1·47; p<0·0001). There was no difference in adverse event-related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among the 417 patients who continued, uptitration occurred more frequently among control participants than intervention participants (p<0·0001). However, at 52 weeks mean unattended systolic blood pressure remained lower by 7·7 mm Hg (95% CI 5·2-10·3) and blood pressure control rates higher in the intervention group (81%) versus control group (62%; RR 1·32, 95% CI 1·16-1·50). In all randomly assigned participants up to 12 weeks, there were seven (3%) serious adverse events in the intervention group and three (1%) serious adverse events in the control group. INTERPRETATION: A strategy with early treatment of a fixed-dose quadruple quarter-dose combination achieved and maintained greater blood pressure lowering compared with the common strategy of starting monotherapy. This trial demonstrated the efficacy, tolerability, and simplicity of a quadpill-based strategy. FUNDING: National Health and Medical Research Council, Australia.

Ultra-low-dose quadruple combination blood pressure-lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control, although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of 4 blood pressure-lowering agents each at a quarter dose may provide a simple, safe, and effective blood pressure-lowering solution which may also improve long-term adherence. The Quadruple UltrA-low-dose tReaTment for hypErTension (QUARTET) double-blind, active-controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline-recommended standard care in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg or to control therapy of a single identical-appearing pill containing irbesartan 150 mg. In both arms, step-up therapy of open-label amlodipine 5 mg will be provided if blood pressure is >140/90 at 6 weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12-week follow-up. The primary outcome and some secondary outcomes will be assessed at 12 weeks; there is an optional 12-month extension phase to assess longer-term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects, and has better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure.

Impact of the COVID-19 pandemic on the management of chronic heart failure.

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented challenge. Meeting this has resulted in changes to working practices and the impact on the management of patients with heart failure with reduced ejection fraction (HFrEF) is largely unknown. We performed a retrospective, observational study contrasting patients diagnosed with HFrEF attending specialist heart failure clinics at a UK hospital, whose subsequent period of optimisation of medical therapy was during the COVID-19 pandemic, with patients diagnosed the previous year. The primary outcome was the change in equivalent dosing of ramipril and bisoprolol at 6-months. Secondary outcomes were the number and type of follow-up consultations, hospitalisation for heart failure and all-cause mortality. In total, 60 patients were diagnosed with HFrEF between 1 December 2019 and 30 April 2020, compared to 54 during the same period of the previous year. The absolute number of consultations was higher (390 vs 270; p = 0.69), driven by increases in telephone consultations, with a reduction in appointments with hospital nurse specialists. After 6-months, we observed lower equivalent dosing of ramipril (3.1 ± 3.0 mg vs 4.4 ± 0.5 mg; p = 0.035) and similar dosing of bisoprolol (4.1 ± 0.5 mg vs 4.9 ± 0.5 mg; p = 0.27), which persisted for ramipril (mean difference 1.0 mg, 95% CI 0.018-2.09; p = 0.046) and bisoprolol (mean difference 0.52 mg, 95% CI -0.23-1.28; p = 0.17) after adjustment for baseline dosing. We observed no differences in the proportion of patients who died (5.0% vs 7.4%; p = 0.59) or were hospitalised with heart failure (13.3% vs 9.3%; p = 0.49). Our study suggests the transition to telephone appointments and re-deployment of heart failure nurse specialists was associated with less successful optimisation of medical therapy, especially renin-angiotensin inhibitors, compared with usual care.

Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users.

Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

An attempt at administering a transdermal formulation of bisoprolol in patients with acute cardiac symptoms.

BACKGROUND: Bisono® is the world's first transdermal formulation of a bisoprolol, which is approved for the treatment of hypertension in Japan. We aimed to investigate the usefulness of this formulation in patients who were admitted to our hospital with cardiac symptoms suggestive of acute coronary syndrome or an acute exacerbation of heart failure. METHODS: This study involved a retrospective survey of medical records from September 1, 2017 to April 30, 2018 obtained from the Cardiovascular Center of Kyoto Katsura Hospital. The clinical data of patients on admission who had received a transdermal formula of bisoprolol (Bisono® tape) were retrieved; their blood pressure and heart rate data were analyzed in relation to the doses of Bisono® tape administered. RESULTS: Sixty-three patients received the Bisono® tape. Their final diagnoses included acute myocardial infarction, an exacerbation of heart failure, and atrial fibrillation. While there was no significant correlation observed between the administered doses of the drug and reduction in blood pressure achieved within 24 h after admission, there was a significant (p < 0.05) correlation between the doses of Bisono®tnd reduction in the heart rate within 24 h after admission (ΔHR0-24 h). Only one patient who received 8 mg of Bisono® exhibited temporal bradycardia (heart rate < 50 bpm). CONCLUSION: The transdermal formulation of bisoprolol may be useful for the early introduction of ß-blockers in patients admitted with cardiac symptoms associated with myocardial ischemia or heart failure. However, caution should be exercised because of the possible risk of hypotension.

Effects of Bisoprolol Transdermal Patches for Prevention of Perioperative Myocardial Injury in High-Risk Patients Undergoing Non-Cardiac Surgery　- Multicenter Randomized Controlled Study.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of transdermal ß-blocker patches, which offer stable blood concentration and easy availability during operation, for prevention of perioperative myocardial injury (PMI) in high-risk patients.Methods and Results:In this randomized controlled trial, patients aged >60 years with hypertension and high revised cardiac risk index (≥2) undergoing non-cardiac surgery were randomly assigned to a bisoprolol patch or control group. Primary efficacy outcome was incidence of PMI, defined as postoperative high-sensitivity cardiac troponin T (hs-cTnT) >0.014ng/mL and relative hs-cTnT change ≥20%. Secondary efficacy outcomes were number of cardiovascular events and 30-day mortality. From November 2014 to February 2019, 240 patients from 5 hospitals were enrolled in this study. The incidence of PMI was 35.7% in the bisoprolol patch group and 44.5% in the control group (P=0.18). Incidence of major adverse cardiac events including non-critical myocardial infarction, strokes, decompensated heart failure and tachyarrhythmia was similar between the 2 groups. Tachyarrhythmia tended to be higher in the control group. There were no significant differences in safety outcomes including significant hypotension and bradycardia requiring any treatment between the 2 groups. CONCLUSIONS: Bisoprolol patches do not influence the incidence of PMI and cardiovascular events in high-risk patients undergoing non-cardiac surgery, but perioperative use of these patches is safe.

Bisoprolol transdermal patch improves orthostatic hypotension in patients with chronic heart failure and hypertension.

ß blockers (BBs) play an important role in heart failure (HF) treatment. However, orthostatic hypotension (OH) is sometimes caused by BBs. The bisoprolol transdermal patch works more slowly and is long acting compared with the bisoprolol fumarate tablet. The risk of OH may be reduced by using the bisoprolol transdermal patch. We evaluated 57 consecutive patients who were taking the bisoprolol fumarate tablet for chronic HF with hypertension from November 2016 to September 2017. We switched the patients to the bisoprolol transdermal patch. Because 12 of 57 subjects could not continue using the bisoprolol transdermal patch, we analyzed the remaining 45 patients. We investigated BP, blood tests, and changes in BP from supine to standing positions before and after 6 months of switching from tablet to patch. OH was diagnosed by observing a systolic/diastolic BP drop of at least 20/10 mmHg or an absolute systolic BP (sBP) of <90 mmHg from the standing position. No significant changes were observed in the BP and BPs from supine to standing positions, whereas log brain natriuretic peptide was significantly reduced after switching from patch to tablet (2.102 to 2.070pg/dl, P = .039). OH, which occurred in originally 17 patients, showed improvement and eventually appeared in 4 patients. In these patients, changes in BP from supine to standing positions were also significantly improved (changes in sBP, -11 to -6mmHg, P = .016). This study demonstrated that switching from the bisoprolol fumarate tablet to transdermal patch reduced the morbidity of OH in HF patients.

Comparison of the Transdermal Bisoprolol Patch with Oral Bisoprolol Fumarate Administration as a Therapeutic Agent for Idiopathic Frequent Premature Ventricular Contractions.

The transdermal bisoprolol patch (TB) was designed to maintain a sustained concentration of bisoprolol in plasma by a higher trough concentration than oral bisoporolol (OB). We compared the efficacy between TB and OB in patients with idiopathic premature ventricular contractions (PVCs) while considering their duration of action.A total of 78 patients with a PVC count of ≥ 3,000 beats/24 hours were divided into groups treated with TB 4 mg (n = 43) or OB 2.5 mg (n = 35). PVCs were divided into positive heart rate (HR) -dependent PVCs (P-PVCs) and non-positive HR-dependent PVCs (NP-PVCs) based on the relationship between the hourly PVC density and hourly mean HR. Twenty-four-hour Holter electrocardiograms were performed before and 1 to 3 months after the initiation of therapy.There were no significant between-group differences in the baseline characteristics. Both the TB (from 14.6 [9.9-19.2] to 7.6 [1.7-15.8]%, P < 0.001) and OB (from 13.2 [7.6-21.9] to 4.6 [0.5-17.0]%, P = 0.0041) significantly decreased the PVC density, and there was no significant difference between the two groups (P = 0.73). Compared to OB, the TB had similar effects in reducing the PVC density for P-PVCs (P = 0.96), and NP-PVCs (P = 0.71). The TB significantly decreased the P-PVC density from baseline not only during day-time (P < 0.001) but also night-time (P = 0.0017), while the OB did not significantly decrease the P-PVC density from baseline during night-time (P = 0.17).Compared to OB, the TB could be used with the same efficacy of reducing idiopathic PVCs. The TB may be a more useful therapeutic agent than OB for P-PVCs during a 24-hour period.

Association Between Dose and Plasma Concentration of Bisoprolol in Patients with Heart Failure (CVI ARO 6).

Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.

Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014).

BACKGROUND AND PURPOSE: In our institute, breast cancer patients undergoing adjuvant treatment are included in a protocol aimed to reduce cardiovascular morbidity (SAFE-2014, NCT2236806), assessing preclinical heart damage with heart speckle-tracking ultrasound. To develop a dose constraint related to subclinical heart damage, a reliable delineation of heart substructures based on a pre-existing guideline was made. PATIENTS AND METHODS: Heart substructures of 16 left-sided breast cancer patients included in the SAFE protocol were delineated by five operators. For each substructure, a multi-contour delineation based on a majority vote algorithm (MCD) was created. A consensus-based delineation (CBD) was developed by an independent team of two blinded operators. Dice similarity coefficients (DSC) between volumes delineated by different operators and the MCD were collected and reported, as well as DSC between CBD and MCD. RESULTS: Mean DSCs between heart chambers delineated by each operator and the corresponding MCDs ranged between 0.78 and 0.96. Mean DSC between substructures delineated by all single operators and the corresponding MCD ranged between 0.84 and 0.94. Mean DSC between CBD and the corresponding MCD ranged from 0.89 to 0.97. CONCLUSION: Results showed low inter-observer variability of heart substructure delineation. This constitutes an external validation of the contouring atlas used, allowing a reliable dosimetric assessment of these volumes within the SAFE-2014 trial.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

Tolerability, Efficacy, and Safety of Bisoprolol vs. Carvedilol in Japanese Patients With Heart Failure and Reduced Ejection Fraction　- The CIBIS-J Trial.

BACKGROUND: The comparative tolerability, efficacy, and safety of bisoprolol and carvedilol have not been established in Japanese patients with heart failure and reduced ejection fraction (HFrEF). Methods and Results: The CIBIS-J trial is a multicenter, open-label, non-inferiority randomized controlled trial of bisoprolol vs. carvedilol in 217 patients with HFrEF (EF ≤40%). The primary endpoint was tolerability, defined as reaching and maintaining the maximum maintenance dose (bisoprolol 5 mg/day or carvedilol 20 mg/day) during 48 weeks of treatment. The primary endpoint was achieved in 41.4% of patients in bisoprolol (n=111) and 42.5% in carvedilol (n=106) groups. The non-inferiority of tolerability of bisoprolol compared with carvedilol was not supported, however, neither ß-blocker was superior with regard to tolerability. Heart rate (HR) decreased in both groups and its decrease from baseline was significantly greater in the bisoprolol group (20.3 vs. 15.4 beats/min at 24 week, P<0.05). Plasma B-type natriuretic peptide (BNP) levels decreased in both groups and the decrease was significantly greater in the carvedilol group (12.4 vs. 39.0 % at 24 weeks, P<0.05). CONCLUSIONS: There were no significant differences between bisoprolol and carvedilol in the tolerability of target doses in Japanese HFrEF patients. The clinical efficacy and safety were also similar despite the greater reduction in HR by bisoprolol and plasma BNP by carvedilol.

Bisoprolol transdermal patch for perioperative care of non-cardiac surgery in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Non-cardiac surgery for hypertrophic obstructive cardiomyopathy (HOCM) is considered to require meticulous perioperative care. ß-blockers are considered the first-line drugs for patients with HOCM, and they play a key role in preventing cardiovascular complications in perioperative care. The bisoprolol transdermal patch has recently become available in Japan, and it is useful for patients who are unable to take oral medication during perioperative care. The aim of this case series was to assess the hemodynamic features of patients with HOCM who used the bisoprolol transdermal patch during perioperative care for non-cardiac surgery. METHODS: Between August 2016 and August 2018, we retrospectively analyzed 10 consecutive cases of HOCM with the patients using the bisoprolol transdermal patch during perioperative care. Hemodynamic and echocardiographic features were evaluated before and after patients were switched from oral bisoprolol to transdermal patch therapy or started transdermal patch therapy as a new ß-blocker medication. In addition, cardiovascular complications (all-cause death, cardiac death, heart failure, ventricular tachycardia, and ventricular fibrillation) during the perioperative period were evaluated. RESULTS: There was no significant change in the patients' heart rate, blood pressure, ejection fraction, and pressure gradient in the left ventricle after switching from oral bisoprolol to the transdermal patch therapy. On the other hand, patients who started using the bisoprolol transdermal patch as a new ß-blocker medication tended to have a decreased heart rate and pressure gradient thereafter, but there was no significant difference in blood pressure or ejection fraction. No cardiovascular complications occurred during the perioperative period. CONCLUSIONS: We described the utilization of the bisoprolol transdermal patch during perioperative care for non-cardiac surgery in patients with HOCM. We determined that the hemodynamic features of these patients did not change significantly after switching to patch therapy. Further, initiation of the bisoprolol transdermal patch as a new ß-blocker medication sufficiently tended to decrease the pressure gradient. This unique approach can be an alternate treatment option for HOCM. TRIAL REGISTRATION: The registry was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000036703). The date of registration was 10/5/2019 and it was "Retrospectively registered".

Supraventricular tachyarrhythmias that responded dramatically to bisoprolol transdermal patches in two patients undergoing hemodialysis.

We here report two patients with atrial flutter (AFL) and paroxysmal supraventricular tachycardia (PSVT) who were undergoing hemodialysis and returned quickly to normal sinus rhythm without hypotension when treated with bisoprolol transdermal patches (Bisono® Tape) (TOA EIYO, Tokyo, Japan). Spontaneous rhythm reversion had not occurred prior to these events in either patient. Our findings indicate that Bisono® Tape may be a new and more effective treatment for AFL and PSVT in patients undergoing hemodialysis.

Catheter ablation vs. antiarrhythmic drug therapy in patients with symptomatic atrioventricular nodal re-entrant tachycardia: a randomized, controlled trial.

AIMS: To conduct a randomized trial in order to guide the optimum therapy of symptomatic atrioventricular nodal re-entrant tachycardia (AVNRT). METHODS AND RESULTS: Patients with at least one symptomatic episode of tachycardia per month and an electrophysiologic diagnosis of AVNRT were randomly assigned to catheter ablation or chronic antiarrhythmic drug (AAD) therapy with bisoprolol (5 mg od) and/or diltiazem (120-300 mg od). All patients were properly educated to treat subsequent tachycardia episodes with autonomic manoeuvres or a 'pill in the pocket' approach. The primary endpoint of the study was hospital admission for persistent tachycardia cardioversion, during a follow-up period of 5 years. Sixty-one patients were included in the study. In the ablation group, 1 patient was lost to follow-up, and 29 were free of arrhythmia or conduction disturbances at a 5-year follow-up. In the AAD group, three patients were lost to follow-up. Of the remainder, 10 patients (35.7%) continued with initial therapy, 11 patients (39.2%) remained on diltiazem alone, and 7 patients (25%) interrupted their therapy within the first 3 months following randomization, and subsequently developed an episode requiring cardioversion. During a follow-up of 5 years, 21 patients in the AAD group required hospital admission for cardioversion. Survival free from the study endpoint was significantly higher in the ablation group compared with the AAD group (log-rank test, P < 0.001). CONCLUSIONS: Catheter ablation is the therapy of choice for symptomatic AVNRT. Antiarrhythmic drug therapy is ineffective and not well tolerated.

Efficacy and Safety of Switching From Oral Bisoprolol to Transdermal Patch in Japanese Patients With Chronic Heart Failure.

BACKGROUND: TY-0201 (TY) is a transdermal formulation of bisoprolol that is the free base of bisoprolol fumarate (BO), a drug widely used to treat chronic heart failure (CHF). The objectives of this phase II study were to evaluate the efficacy and safety of TY when switching from oral BO to TY in patients with CHF whose drug therapy was optimized, and to determine the dose conversion rate of BO to TY.Methods and Results:The efficacy and safety of once daily TY patch use for 16 weeks was investigated in 40 patients with CHF who were stabilized with an optimized drug treatment, including BO, after switching from BO to TY at the dose conversion rate of 5:8. The pre-switch left ventricular ejection fraction was 50.13±11.09% (mean±SD). The post-switch value was 50.87±10.79% after 16 weeks, which was not significantly different, with similar results for other efficacy and safety parameters. The 16-week study was continued for all patients without changing doses after switching to TY. No cardiovascular deaths, hospitalizations for worsening HF, or significant safety concerns were observed. CONCLUSIONS: Efficacy was maintained without significant safety concerns in patients with CHF who were stabilized with BO treatment after switching to TY, suggesting the appropriateness of the dose conversion rate.

EFFECT OF HYDROPHILIC AND HYDROPHOBIC POLYMER ON IN VITRO DISSOLUTION AND PERMEATION OF BISOPROLOL FUMARATE THROUGH TRANSDERMAL PATCH.

A matrix transdermal patch of bisoprolol fumarate was formulated with different concentrations of Eudragit RS 100 and Methocel E5 with PEG 400 as plasticizer by solvent evaporation technique. Tween 80 was added to the optimized patch to evaluate the effect of permeation enhancer at different concentration through the excised rabbit's skin. The patches were analyzed for weight variation, drug content, swelling index, erosion studies, moisture content, moisture uptake, water vapor transmission rate (WVTR) and water vapor permeability (WVP). In vitro dissolution test was carried out in USP dissolution apparatus V to select the optimized formulation. In vitr skin permeation studies were done in Franz diffusion cell using rabbit skin as a model membrane. The cumulative drug release and flux were determined to compare the result of test patches with a control patch. The greatest enhancement ratio (ER) was obtained in F03-PE with 30% Tween 80. F03-PE seemed to follow zero order kinetics with super case II mechanism of drug release. Statistical ANOVA suggested that there was a significant difference in formulations, steady flux and cumulative permeation rate at different Tween 80 concentrations.

[Efficacy of Transdermal Patch of Bisoprolol for Paroxysmal Atrial Fibrillation after Open Heart Surgery].

2014 American Association for Thoracic Surgery (AATS) guidelines recommend beta blocker for prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures. In recent years, transdermal patch of bisoprolol (TDPB) has become available in Japan. We examined the efficacy of TDPB for paroxysmal atrial fibrillation (PAF) after open heart surgery. Among 289 patients who had undergone open heart surgery in our hospital from December 2013 to April 2016, 48(16.6%)patients, for whom TDPB was used for PAF, were analyzed retrospectively. The summary of our PAF protocol:HR >80;a sheet of TDPB (4 mg) is pasted, HR≤60;TDPB is removed, HR >140 persisted;another sheet of TDPB is added. Eighteen of the 48 (37.5%) patients recovered sinus rhythm within 24 hours. Six patients( 12.5%), because of persistent tachycardia, shifted to continuous infusion of landiolol. Ten underwent electrical defibrillation during hospitalization. In 3 patients, TDPB was removed due to advanced bradycardia. TDPB could be used safely and feasibly for PAF after open heart surgery.

[COSYREL - an efficient fixed combination for treatment of hypertension, stable ISHD and heart failure]. / COSYREL - úcinná fixní kombinace pro lécbu hypertenze, stabilní ICHS a srdecního selhání.

Fixed combinations of two or three drugs are being frequently used in cardiovascular diseases. This approach markedly increases adherence of the patients to prolonged therapy and thus leads to better control of the diseases. Fixed combinations are often used in hypertension and coronary artery disease (CAD). Cosyrel is the first fixed combination of betablocker (bisoprolol fumarat) and ACE inhibitor (perindopril arginin) available in czech market. The advantage is availability in several concentrations (10 mg/10 mg, 10 mg/5 mg a 5 mg/10 mg a 5 mg/5 mg) , when first indicates bisoprolol dose and the second perindopril. This combination is indicated in arterial hypertension and/or in stable CAD (in patients after myocardial infarction or revascularisation) and/or in dosages 5 mg/5 mg and 5 mg/10 mg in patients with chronic heart failure with systolic dysfunction. This article aimed to evaluate briefly clinical characteristics of this fixed combination. Bisoprol and perindopril arginin have a lot of data indication their positive impact on CV risk and prognosis.Key words: bisoprolol - coronary artery disease - heart failure - hypertension - perindopril.